Project Summary Chronic kidney disease affects millions of Americans and leads to many hormonal abnormalities, including elevations in the phosphate regulating hormone fibroblast growth factor 23 (FGF23). FGF23 is classically thought to be produced by bone cells, but recent reports suggest other tissues may also make FGF23. Elevated FGF23 levels may lead to increased mortality and accelerated loss of kidney function in patients with chronic kidney disease. FGF23 levels are also increased in individuals with acute kidney dysfunction and may lead to increased mortality. Importantly, the mechanisms that lead to high FGF23 levels in acute or chronic loss of kidney function are not well understood. The PI's overall objective is to define the mechanisms controlling FGF23 production with the long-term goal of reducing morbidity and mortality in the kidney disease population. To achieve this objective, the PI proposes to use new genetically modified mice where the FGF23 gene has been deleted from different groups of bone cells to better define the contribution of bone versus other tissues in the elevated levels of FGF23 seen in states of acute and chronic kidney disease. Specifically, Aim1 will determine the contribution of bone cells to FGF23 levels in acute kidney injury, and the effects of immune system suppression on this production. Aim2 will determine the contribution of bone cells to FGF23 elevation in chronic kidney disease.